HCl/DMSO/HFIP-Mediated Chlorination of Pyrrolo[2,1-a]isoquinolines and Other Electron-Rich Heteroarenes.

An efficient oxidative chlorination of pyrrolo[2,1-a]isoquinolines has been established using HCl (aq) as the chlorine source and DMSO as the terminal oxidant in HFIP at ambient temperature. A variety of chlorinated pyrrolo[2,1-a]isoquinoline derivatives have been prepared readily in 23 to 99% yields. This chlorination strategy can be expanded to the functionalization of other electron-rich heteroarenes including substituted pyrroles, indoles, and naphthols.

TBHP/Et3N-Promoted Chemoselective Formylation and Peroxidation of Pyrrolo[2,1-a]isoquinolines.

An efficient formylation of pyrrolo[2,1-a]isoquinoline derivatives has been reached by the use of TBHP (tBuOOH) and Et3N as the mediator. In this strategy, CHO and CDO can be readily incorporated into heteroarenes by the utilization of CHCl3 and CDCl3 as the carbonyl sources. Interestingly, a solvent-controlled chemoselectivity was observed. The use of PhCl as a solvent resulted in dearomatization and peroxidation of pyrrolo[2,1-a]isoquinolines, delivering functionalized peroxides in 53-64% yields.

Recent advances in oxidative chlorination.

Considering the wide occurrence and extensive application of organic chlorides in many research fields, the development of easy, practical and green chlorination methodologies is much needed. In the oxidative chlorination strategy, active chlorinating species can be in situ formed by the interaction of easily accessible chlorides such as NaCl, HCl, KCl, CHCl3, etc. and suitable oxidants. Among the established chlorination approaches, this strategy is an attractive one as it features the use of readily available, cheap and safe inorganic or organic chlorides, good atom economy of chlorine, and multiple choices of oxidants. This review summarizes the representative methodologies in the field of oxidative chlorination, covering 2013 to 2023.

POCl3/Sulfoxide-Promoted Synthesis of Indolizino[8,7-b]indoles.

A mild chlorocyclization of pyrrole-tethered indoles has been realized using POCl3 as the chlorine source and tetramethylene sulfoxide as the promoter. A variety of chlorinated indolizino[8,7-b]indole derivatives have been constructed efficiently under this reaction system in moderate to good yields (19 examples, up to 93% yield).

Iron-Catalyzed Synthesis of Peroxylpyrrolo[2,1-a]isoquinolines through Oxidative Dearomatization.

A mild late-stage modification of pyrrolo[2,1-a]isoquinolines was established through iron-catalyzed oxidative dearomatization and peroxidation. Peroxylated pyrroloisoquinolines have been prepared readily with hydroperoxide in low to good yields (up to 72%) at room temperature. Interestingly, the treatment of fully aromatized pyrrolo[1,2-a]quinolines under the current reaction system resulted in the formation of ring-opening products.

NH4OAc/DMSO-Promoted Benzylation of Pyrrolo[2,1-a]isoquinolines.

Benzylation of pyrrolo[2,1-a]isoquinoline derivatives has been realized with various phenols by the use of ammonium acetate as a promoter (20 examples, up to 84% yield). DMSO served as the source of methylene and solvent. The employment of iron chloride as a catalyst can also afford the desired benzylated products in moderate to good yields (11 examples, up to a 74% yield).

POCl3/Sulfoxide and AcCl/Sulfoxide Mediated Chlorination of Pyrrolo[2,1-a]isoquinolines.

We have developed an efficient chlorination of pyrrolo[2,1-a]isoquinoline derivatives using POCl3 as the chlorine source and tetramethylene sulfoxide as a promoter. A series of pyrrolo[2,1-a]isoquinolines, polysubstituted pyrroles, and naphthols have been readily chlorinated under mild reaction conditions (26 examples, up to >99% yield). AcCl can also act as the chlorine source competently in this chlorination reaction.

AcBr/DMSO Mediated Sulfenylation of Pyrrolo[2,1-a]isoquinolines.

We have developed a mild sulfenylation of pyrrolo[2,1-a]isoquinolines with acetyl bromide and dimethyl sulfoxide. A wide range of functionalized pyrrolo[2,1-a]isoquinolines could be prepared efficiently through the formation of a C-S bond with thiophenols (27 examples, 36-94% yields). The current strategy can also be utilized for functionalization of pyrrolo[1,2-a]quinolines and indole.

Nitration of Pyrrolo[2,1-a]isoquinolines.

We have successfully modified a series of pyrrolo[2,1-a]isoquinolines via direct nitration under mild reaction conditions. Easily accessible nitrates including CAN, Cu(NO3)2·H2O, and Fe(NO3)3·9H2O all can serve as effective nitrating reagents for functionalizing pyrrolo[2,1-a]isoquinolines. Various nitro-bearing pyrrolo[2,1-a]isoquinolines have been efficiently prepared in acceptable to good yields.

Bromination of Pyrrolo[2,1-a]isoquinolines with Acetyl Bromide and Dimethyl Sulfoxide.

A mild bromination of pyrrolo[2,1-a]isoquinolines has been achieved using acetyl bromide and dimethyl sulfoxide. A series of brominated pyrrolo[2,1-a]isoquinolines could be obtained in moderate to excellent yields (46-99%) at room temperature. This strategy can also be expanded to the facile bromination of polysubstituted pyrroles, indoles, electron-rich phenols, aniline, and 2-naphthol.

Recent progress in the oxidative bromination of arenes and heteroarenes.

Oxidative bromination has been serving as a powerful tool for the synthesis of bromo-containing molecules, as this bromination strategy features environmental friendliness, high flexibility in reaction system design and wide abundance of bromide sources and oxidants. The past decade has witnessed a large number of efficient oxidative bromination reaction systems and novel brominated aromatics. This review summarizes recent developments in the field of oxidative preparation of bromoarenes and bromoheteroarenes covering from 2012 to 2022.

Recent Advances in DMSO-Based Direct Synthesis of Heterocycles.

Besides serving as a low-toxicity, inexpensive and easily accessible solvent, dimethyl sulfoxide (DMSO) has also been extensively used as a versatile reagent for the synthesis of functionalized molecules. Dimethyl sulfoxide can not only be utilized as a carbon source, a sulfur source and an oxygen source, but also be employed as a crucial oxidant enabling various transformations. The past decade has witnessed a large number of impressive achievements on the direct synthesis of heterocycles as well as modifications of heterocyclic compounds by applying DMSO as a reagent. This review summarized the DMSO-based direct heterocycle constructions from 2012 to 2022.

Synthesis of Pyrrolo[2,1-a]isoquinolines through Cu-Catalyzed Condensation/Addition/Oxidation/Cyclization Cascade.

We have developed a copper-catalyzed synthesis of pyrrolo[2,1-a]isoquinolines with terminal alkynes, aldehydes, and tetrahydroisoquinolines. A variety of pyrrolo[2,1-a]isoquinolines have been prepared in 17-69% yield via a condensation/Mannich-type addition/oxidation/cyclization cascade sequence. Modifications through simple chemical transformations provided highly functionalized molecules containing a privileged framework.

Modification of Pyrrolo[2,1-a]isoquinolines and Polysubstituted Pyrroles via Methylenation with Acetyl Chloride and Dimethylsulfoxide.

A convenient synthesis of methylene-bridged pyrrolo[2,1-a]isoquinolines has been developed. Treatment of pyrroloisoquinolines with acetyl chloride and dimethylsulfoxide (DMSO) at ambient temperature afforded bispyrroloisoquinolylmethanes in 17-85% yields. This reaction system can also be expanded to the synthesis of bispyrrolylmethanes (34-94% yields). Easy chemical transformation of methylene-bridged pyrroloisoquinoline provided an unsymmetric acid and amide possessing a privileged framework.

Recent progress in the synthesis of pyrrolo[2,1-a]isoquinolines.

Pyrrolo[2,1-a]isoquinolines occur frequently in a large number of bioactive natural products and pharmaceutically important molecules. The synthesis of pyrrolo[2,1-a]isoquinoline derivatives is an easy and useful way to produce artificial molecules with potential applications. A huge number of excellent methodologies for constructing pyrrolo[2,1-a]isoquinolines have been reported in the last decade. This review summarizes the recent advances in this research field covering from 2011 to 2021.

Modification of Pyrrolo[2,1-a]isoquinolines and Pyrrolo[1,2-a]quinolines with Ammonium Acetate and Dimethyl Sulfoxide via Methylthiomethylation.

An efficient methylthiomethylation of pyrroloisoquinolines and pyrroloquinolines has been reached by the use of ammonium acetate and dimethyl sulfoxide. Methylthiomethylated heterocycles can be obtained in moderate to good yields in most cases, while trace amounts to good yields of methylene-bridged products can be observed. Choice of DMSO activator and its amount have a great influence on the chemoselectivity of this process. It is worth noting that this process can also be scalable. Another feature of this process is that the product can be transformed to sulfone and sulfoxide easily.

Formylation and Bromination of Pyrrolo[2,1-a]isoquinoline Derivatives with Bromoisobutyrate and Dimethyl Sulfoxide.

We have developed an efficient formylation of pyrroloisoquinolines using bromoisobutyrate and dimethyl sulfoxide as carbonyl reagent. Various formylated pyrroloisoquinolines could be prepared in good yields (up to 94%). This formylation process can be easily scaled up to gram scale with good yield. In most cases of pyrroloisoquinolines without methoxy groups, the combination of bromoisobutyrate and dimethyl sulfoxide could act as a bromination reagent, delivering brominated pyrroloisoquinolines in acceptable to good yields (up to 82%).

Synthesis of Tetrahydroindolizino[8,7-b]indole Derivatives in the Presence of Fe(OTf)3 or CF3SO3H through Intramolecular Dearomatization of Indole.

We have developed a convenient synthesis of tetrahydroindolizino[8,7-b]indole derivatives via intramolecular dearomatization of indole. Highly functionalized tetrahydroindolizinoindoles can be prepared in the presence of trifluoromethanesulfonic acid in good to excellent yields (up to >99% yield) with novel designed pyrrole-tethered indoles. The same products can also be synthesized through a mild Fe(OTf)3-catalyzed process in acceptable to good yields (up to 75% yield).

FeCl2 catalyzed direct modification of dihydropyrrolo[2,1-a]isoquinolines with phenols.

A mild catalytic modification of dihydropyrrolo[2,1-a]isoquinolines with various phenols via the formation of heteroarene cation radicals as key intermediates has been developed. A range of direct cross-coupling products could be obtained in acceptable to excellent yields (up to 98%) in the presence of FeCl2.

Recent progress in (hetero)arene cation radical-based heteroarene modification.

The transformation of (hetero)arene cation radicals has become a powerful tool for the construction of highly functionalized (hetero)arenes. These (hetero)arene cation radicals could be generated under electrochemical, photochemical or chemical oxidation systems. The in situ generated (hetero)arene cation radicals can be attacked by various nucleophiles, such as (hetero)aromatics and anions, yielding structurally diverse molecules. Recently, a large number of impressive heteroarene modifications have been designed by this strategy. This review summarizes the advances in heteroarene modification via reactions of in situ formed (hetero)arene cation radicals, ranging from 2010 to 2020.